Throughout this application, various publications are referenced by Arabic numerals. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the art to which this invention pertains.
Mammalian reproduction requires a physiological stimulation of male erectile tissues in the penis to mechanistically support the transfer of sperm from the male to the female. obviously then, defects that prevent an appropriate erectile tissue response can drastically interfere with reproductive capability. In humans, erectile dysfunction is considered to be a disease state and is referred to as the condition of xe2x80x9cimpotencexe2x80x9d. This condition impacts on the quality of life both of the male patients, as well as their wives/partners (1).
Erection is a hemodynamic phenomenon involving the tissue of the corpora cavernosa as well as the corpus spongiosum in the penis. This tissue is a complex admixture of smooth muscle, endothelial cells, fibroblasts and nerves interacting under stimulatory conditions to drastically enhance and maintain an accessory blood supply that imparts rigidity to the penis. Given the need for stringent control of blood flow during this response, it is no surprise that vascular insufficiency has the ability to drastically suppress erectile capability. In fact, penile vascular insufficiency is believed to be a very common pathomechanism of erectile dysfunction (2). This is associated with substantial pathologic changes in the erectile tissue leading to reduction in vascular smooth muscle cells and increases in collagen and fibrosis (3-6).
The currently available treatments of erectile dysfunction induce temporary erections at the same time of administration of such treatments. However, these treatments do no address or cure the basic vascular/cavernosal pathology causing erectile dysfunction. The rationale for a curative treatment that improves or repairs the vascular structure and function of the erectile tissue is based upon the understanding of erectile physiology and the pathophysiology of vascular erectile dysfunction. Consequently, it is prudent to pursue investigation of factors,hat induce new vascular structure formation or vasculogenesis. Several naturally occurring growth factors have been found to induce vasculogenesis (7-10). Such growth factors include the vascular endothelial growth factor (VEGF) family (11), the fibroblast growth factor (FGF) family (12, 13), transforming growth factor -alpha and -beta (TGF) (14), and platelet derived growth factor (PDGF) (15-17). Vascular endothelial growth factor (VEGF) may well be one of the most potent and interesting of these vascular growth factors. It is thought to play a role in embryonic vasculogenesis (18), maintenance of vascular structures in the adult and formation of new blood vessels in the adult in responses to ischemia and other pathologic states. Therapies that increase tissue levels of VEGF in laboratory animals or humans with peripheral vascular disease have resulted in a measurable increase in tissue vascularity (19-24).
In order to contemplate the potential of VEGF therapy for erectile dysfunction, a characterization was wanted of the extent to which VEGF is expressed in the mammalian penis and in erectile tissue, as well as a determination of which of the known isoforms of VEGF (derived from mRNA splice site variation) are most abundantly present in this tissue compared to other mammalian tissues. Here a survey of VEGF isoform expression (mRNA) in mature rat penis and in human erectile tissue is presented.
VEGF is a growth factor that acts preferentially on endothelial cells(18) . With the current focus of biomedical research on angiogenesis, the biology of VEGF has been under intense scrutiny. In humans, there are several different genes that encode VEGF-like proteins (49,50) , the most studied of these genes is that for VEGF-A (51, 52, 53). As described by several different laboratories, the VEGF-A gene gives rise to several different mature mRNA transcripts that differ in the protein products they encode (33, 34). These variant transcripts arise through an alternative splicing mechanism (30, 31, 54) and the abundance of any particular VEGF-A transcript differs, depending on the tissue examined (28). The most predominant VEGF-A transcripts found in adult tissues encode proteins of 188/189, 164/165 and 120/121 amino acids (rat/human) (28, 35). Other, rarer variant transcripts arising from VEGF-A have also been reported (encoding 205/206 and 144/145 amino acid proteins), but these forms were only found in a few tissues, mainly fetal in origin (VEGF 205/206: human fetal liver (32), sheep (41) and human placenta (42)/VEGF 144/145: human uterus (39), human endometrial carcinoma cells (39), sheep (41) and human placenta (42), respectively). During a preliminary survey of adult penile tissues for the expression of VEGF-A isoforms, it was found that the expression of VEGF-A mRNA splice variants encoding the 205/206 and 144/145 forms of VEGF can be identified by standard RT-PCR techniques and confirmed by cloning and sequencing from other adult rat and human tissues and cultured cells. These results suggest that these rarer splice variants of VEGF-A might have a wider tissue distribution than originally anticipated.
This invention provides a method of increasing or maintaining the blood supply in the penis of a male subject which comprises administering to the subject an amount of vascular endothelial growth factor effective to increase or maintain the blood supply in the subject""s penis.
This invention provides a method of treating erectile dysfunction in a subject which comprises administering to the subject an amount of vascular endothelial growth factor effective to increase the blood supply in the subject""s penis and thereby treat the subject""s erectile dysfunction.
This invention provides a method of increasing or maintaining the density of vascular structures in the penis of a male subject which comprises administering to the subject an amount of vascular endothelial growth factor effective to increase or maintain the blood supply in the subject""s penis.
This invention provides the above methods, wherein the vascular endothelial growth factor is VEGF-A 205/206, VEGF-A 188/189, VEGF-A 164/165, VEGF-A 144/145, VEGF-A 120/121, or VEGF-A 110.
This invention provides the above methods, wherein the vascular endothelial growth factor is administered intravenously, topically, transdermally, orally or by injection.
This invention provides the above methods, wherein the vascular endothelial growth factor is injected into the penis.
This invention provides the above methods, wherein the vascular endothelial growth factor is injected into corpora cavernosa or corpus spongiosum tissue.
This invention provides a method of increasing or maintaining the blood supply in the penis of a subject which comprises introducing a nucleic acid comprising a gene encoding a vascular endothelial growth factor into a suitable cell under conditions such that the nucleic acid expresses vascular endothelial growth factor so as to thereby increase or maintain the blood supply in the subject""s penis.
This invention provides a method of increasing or maintaining the blood supply in the genital area of a female subject which comprises administering to the subject an amount of vascular endothelial growth factor effective to increase or maintain the blood supply in the subject""s genital area.